(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the identification, assessment, and management of side effects of systemic therapies, and a presentation by Dr. Pierre Blanchard discussing the patients who are at risk for long-term non-recovery of testosterone after stopping ADT.
Dr. Blanchard started his presentation with a case of a 72-year-old male with no comorbidities who was diagnosed with high-risk prostate cancer (cT3, Gleason 3+4, PSA 12 ng/mL). At baseline, he was potent with no urinary symptoms. He was treated with external beam radiotherapy + HDR brachytherapy boost + 18 months of ADT (last treatment 6 months ago, a GnRH agonist in September 2014). In 2023, his PSA was <0.01 ng/mL, and testosterone was 0.7 ng/mL.
Testosterone recovery after GnRH agonist from the radiation oncology literature tells us that for short-term ADT it is ~17-18 months versus 24 months for long-term ADT:
In the relugolix HERO trial,1 the testosterone recovery for relugolix (a GnRH antagonist) was much quicker, with a higher testosterone level, compared to leuprolide:
At 8 months of treatment, the following figure emphasizes the minimal effect of abiraterone versus abiraterone + degarelix versus degarelix alone on testosterone recovery:
In the EMBARK trial2 assessing enzalutamide + leuprolide versus enzalutamide versus leuprolide in high-risk non-metastatic hormone-sensitive prostate cancer, during treatment suspension in the combination group and the leuprolide-alone group, testosterone recovered slightly, but not to baseline levels. There was very little effect on testosterone in the enzalutamide monotherapy group. Once treatment resumed in both groups (enzalutamide + leuprolide and leuprolide alone), testosterone levels were reduced:
The impact of radiotherapy on testosterone seems to be modest, with men having a ~30% reduction in testosterone during radiotherapy, and a median recovery time of 6 months to >90% of baseline. Dr. Blanchard summarized this section of his talk discussing testosterone recovery with the following statements:
- Agonists: 6-24 months after end of treatment
- Antagonists: 1-6 months after end of treatment
- There is no impact of concurrent abiraterone or ARPI
- Radiotherapy by itself can lead to testosterone decrease
A recent study from Nabid et al.3 assessed testosterone recovery after ADT in localized prostate cancer by assessing long-term data from two randomized trials. Among 1,230 patients, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of patients recovered normal testosterone on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal testosterone, the median time to testosterone recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with normal testosterone at baseline (p < 0.001):
Factors associated with testosterone recovery on multivariable analysis include baseline normal testosterone, age, diabetes, and duration of ADT:3
Preston and colleagues4 looked at the Optum database to assess the clinical impact of delayed testosterone recovery following the discontinuation of medical ADT. Of 3,875 patients who initiated and discontinued ADT, 1,553 received one or more testosterone-level tests within the 12 months following discontinuation and were included in this study. These 1,553 patients were categorized into two cohorts: 25% as testosterone recovery (testosterone levels >280 ng/dl at any test within 12 months following ADT discontinuation) and 75% as non-testosterone recovery. The testosterone recovery cohort had a lower risk of new-onset diabetes (HR 0.47, 95% CI 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58, 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33, 95% CI 0.99-1.78) versus the non- testosterone recovery cohort:
With regards to the oncologic impact of a longer time to testosterone recovery, Dr. Blanchard discussed a 2009 report by D’Amico and colleagues5 that assessed whether the risk of death is associated with the time to testosterone recovery after radiotherapy and hormonal therapy. Among 102 men randomized to receive radiotherapy and hormone therapy, 57 (56%) had a time to testosterone recovery of >2 years, and none of these men had died of prostate cancer after a median follow-up of 7.6 years. As the time to testosterone recovery increased, the risk of death decreased significantly (aHR 0.60, 95% CI 0.43-0.84; p = 0.003):
Dr. Blanchard summarized this portion of his talk with the following thoughts:
- Time to testosterone recovery is associated with patient age, baseline testosterone, ADT duration, and BMI
- Longer time to recovery impacts general health but may improve DFS in patients without comorbidities
Testosterone replacement therapy recommendations are based on small cohorts and low-level evidence. There is no indication of an increased risk of recurrence, but testosterone replacement therapy should only be given to men with proven testosterone deficiency and bothersome symptoms of hypogonadism. Shared decision-making is paramount due to the theoretical risk of disease recurrence.
Going back to the aforementioned case presentation, Dr. Blanchard notes that in follow-up, the patient was suffering from symptoms of hypogonadism and was referred to endocrinology in 2023. He started testosterone replacement therapy in the spring of 2023, with improvement in sexual function and general well-being. His PSA continues to remain undetectable in spring 2024.
Dr. Blanchard concluded his presentation discussing the patients who are at risk for long-term non-recovery of testosterone after stopping ADT with the following take-home messages:
- Concomitant/adjuvant ADT improves survival in high-risk localized prostate cancer based on studies done with GnRH agonists
- Testosterone recovery is long and uncertain with GnRH agonists and is faster with antagonists
- Time to testosterone recovery is associated with patient age, baseline testosterone, ADT duration, BMI, and comorbidities
- The risk/benefit ratio needs to be discussed when planning testosterone replacement therapy, with careful PSA monitoring
Presenter: Pierre Blanchard, MD, PhD, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Written by: Zachary Klaassen, MD, MSc - Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024.
Related content: Testosterone Recovery After ADT: Timing, Predictive Factors, and Clinical Implications - Pierre Blanchard
References:
- Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196.
- Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2023 Oct 19;389(16):1453-1465.
- Nabid A, Carrier N, Vigneault E, et al. Testosterone recovery after androgen deprivation therapy in localized prostate cancer: Long-term data from two randomized trials. Radiother Oncol. 2024 Mar 27 [Epub ahead of print].
- Preston MA, Hong A, Dufour R, et al. Implications of delayed testosterone recovery in patients with prostate cancer. Eu Urol Open Sci. 2024 Jan 11;60:32-35.
- D’Amico AV, Chen MH, Renshaw AA, et al. Interval to testosterone recovery after hormonal therapy for prostate cancer and risk of death. Int J Radiat Oncol Biol Phys. 2009 Sep 1;75(10):10-15.
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